Efficient Synthesis of â,γ-Dehydrovaline

Unnatural amino acids continue to be the targets of much synthetic interest.1 In particular, â,γ-unsaturated amino acids have been the subject of many synthetic studies because of their interesting biological activity and due to the inherent challenges that are associated with developing efficient synthetic routes to these sensitive compounds. Vinylglycine, the parent compound of this family, has been isolated from mushrooms2 and is postulated to be an intermediate in the enzymatic conversion of homoserine to threonine3 and R-ketobutyrate.4 Several â,γ-unsaturated amino acids have been shown to be irreversible inhibitors of pyridoxal phosphatedependent enzymes and have found use as herbicides and fungicides.5 In addition, â,γ-unsaturated amino acids are of interest because of their unique conformational properties. The majority of the synthetic efforts toward â,γunsaturated amino acids have been directed specifically toward vinylglycine, with few reports describing routes to â,γ-dehydrovaline or other â,γ-unsaturated amino acids. Our laboratory studies antimitotic natural products that bind to microtubules, and we are presently pursuing the total synthesis of phomopsin A (Chart 1). These studies have resulted in new methods to prepare hindered alkyl aryl ethers and R,â-unsaturated amino acids.6 As part of our effort, we required an efficient route to â,γ-dehydrovaline or an appropriately functionalized precursor that could be incorporated into the macrocycle and unveiled at the appropriate time. Many of the reported syntheses of vinylglycine involve oxidative degradation of suitably modified, optically pure R-amino acids (e.g., L-methionine, L-glutamic acid, and L-homoserine);7 however, these methods are not applicable to the synthesis of â,γ-dehydrovaline. More general strategies to prepare â,γ-unsaturated amino acids have been reported,8 including olefination of serine derivatives,9a,b reduction of alkynyl glycine derivatives,9c and Heck coupling approaches.9d However, none of these methods readily lend themselves to the synthesis of â,γdehydrovaline. Two asymmetric syntheses of â,γ-dehydrovaline have been reported to date. The approach utilized by Baldwin et al. entails deconjugation of an R,â-dehydrovaline derivative followed by enzymatic resolution to separate the racemic mixture of enantiomers.10 We initially chose to pursue the second approach reported by Schollkopf, which involves the formation of the bis-lactim ether from glycine and D-valine followed by hydroxyalkylation with acetone and subsequent dehydration.11 In practice, this approach provides a mixture of both R,â-dehydrovaline and â,γ-dehydrovaline. Despite optimization, we achieved as our best result a 3:2 ratio of the two products with the desired unconjugated isomer as the minor component. A more general method to synthesize the desired amino acid was necessary. Of the numerous methods to synthesize derivatives of R-amino acids, the methodology developed by Evans and co-workers is particularly attractive because of its proven utility in numerous applications.12 The most straightforward approach would involve adding the chiral auxiliary to 3-methyl-3-butenoic acid and performing an asymmetric electrophilic amination. However, this transformation is known to generate a mixture of Rand γ-amination products.13 We were also aware of the propensity for â,γ-unsaturated alkenes to migrate into conjugation, so we chose to develop a strategy in which an alkene precursor would be incorporated into the macrocycle precursor and transformed into the desired alkene later in the synthesis. Working with a masked alkene would provide maximum flexibility, which is valuable in the context of a multistep synthesis. Phenylselenide functional groups are labile toward oxidative conditions but are generally stable toward a variety of other conditions, and this robust character makes them particularly attractive for use in the synthesis of complex molecules.14 Elimination of the * To whom correspondence should be addressed. Phone: (650) 7234005. Fax: (650) 725-0259. E-mail: [email protected]. (1) Williams, R. M. Synthesis of optically active R-amino acids; Oxford; New York: Pergamon Press: 1989. (2) Dardenne, G.; Casimir, J.; Marlier, M.; Larsen, P. O. Phytochemistry 1974, 13, 1897. (3) Flavin, M.; Slaughter, C. J. Biol. Chem. 1960, 235, 1112. (4) Posner, B. I.; Flavin, M. J. Biol. Chem. 1972, 247, 6402. (5) (a) Soper, T. S.; Manning, J. M.; Marcotte, P. A.; Walsh, C. T. J. Biol. Chem. 1977, 252, 1571. (b) Rando, R. R. Acc. Chem. Res. 1975, 8, 281. (6) (a) Woiwode, T. F.; Rose, C.; Wandless, T. J. J. Org. Chem. 1998, 63, 9594-9596. (b) Stohlmeyer, M. M.; Tanaka, H.; Wandless, T. J. J. Am. Chem. Soc. 1999, 121, 6100-6101. (7) From L-methionine: (a) Afzali-Ardakani, A.; Rapaport, H. J. Org. Chem. 1980, 45, 4817. Ffrom L-homoserine: (b) Itaya, T.; Shimizu, S.; Nakagawa, S.; Morisue, M. Chem. Pharm. Bull. 1994, 42, 1927. (c) Pellicciari, R.; Natalini, B.; Marinozzi, M. Synth. Commun. 1988, 18, 1715. From L-glutamate: (d) Hannesian, S.; Sahoo, S. P. Tetrahedron Lett. 1984, 25, 1425. (e) Barton, D. H. R.; Crich, D.; Herve, Y.; Potier, P.; Thierry, J. Tetrahedron 1985, 41, 4347. (8) Havlicek, L.; Hanus, J. Collect. Czech. Chem. Commun. 1991, 56, 1365. (9) (a) Beaulieu, P. L.; Duceppe, J. S.; Johnson, C. J. Org. Chem. 1991, 56, 4196. (b) Sasaki, N. A.; Hashimoto, C.; Pauly, R. Tetrahedron Lett. 1989, 30, 1943. (c) Williams, R. M.; Zhai, W. Tetrahedron 1988, 44, 5425. (d) Crisp, G. T.; Glink, P. T. Tetrahedron 1992, 48, 3541. (10) Baldwin, J. E.; Haber, S. B.; Hoskins, C.; Kruse, L. I. J. Org. Chem. 1977, 42, 1239. (11) (a) Schollkopf, U.; Groth, U. Angew. Chem., Int. Ed. Engl. 1981, 20, 977. (b) Schollkopf, U.; Groth, U.; Gull, M.-R.; Nozulak, J. Liebigs. Ann. Chem. 1983, 1133. (12) (a) Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011. (b) Evans, D. A.; Britton, T. C. J. Am. Chem. Soc. 1987, 109, 6881. (13) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F. Tetrahedron 1988, 44, 5525. (14) (a) Reich, H. J. Acc. Chem. Res. 1979, 12, 22. (b) Reich, H. J.; Wollowitz, S. Org. React. 1993, 44, 1. Chart 1 7670 J. Org. Chem. 1999, 64, 7670-7674